VHL Dependent Expression of REDD1 and PDK3 Proteins in Clear-cell Renal Cell Carcinoma.

BACKGROUND: Sporadic clear-cell renal cell carcinoma (ccRCC) is associated with mutations in the VHL gene, upregulated mammalian target of rapamycin (mTOR) activity and glycolytic metabolism. Here, we analyze the effect of VHL mutational status on the expression level of mTOR, eIF4E-BP1, AMPK, REDD1, and PDK3 proteins. METHODS: Total proteins were isolated from 21 tumorous samples with biallelic inactivation, 10 with monoallelic inactivation and 6 tumors with a wild-type VHL (wtVHL) gene obtained from patients who underwent total nephrectomy. The expressions of target proteins were assessed using Western blot. RESULTS: Expressions of mTOR, eIF4EBP1 and AMPK were VHL independent. Tumors with monoallelic inactivation of VHL underexpressed REDD1 in comparison to wtVHL tumors (P = 0.042), tumors with biallelic VHL inactivation (P < 0.005) and control tissue (P = 0.004). Additionally, REDD1 expression was higher in tumors with VHL biallelic inactivation than in control tissue (P = 0.008). Only in wt tumor samples PDK3 was overexpressed in comparison to tumors with biallelic inactivation of VHL gene (P = 0.012) and controls (P = 0.016). In wtVHL ccRCC, multivariate linear regression analysis revealed that 97.4% of variability in PDK3 expression can be explained by variations in AMPK amount. CONCLUSION: Expressions of mTOR, eIF4EBP1 and AMPK were VHL independent. We have shown for the first time VHL dependent expression of PDK3 and we provide additional evidence that VHL mutational status affects REDD1 expression in sporadic ccRCC.

Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study.

BACKGROUND: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. OBJECTIVE: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. RESULTS AND LIMITATIONS: The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R2=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). CONCLUSIONS: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. PATIENT SUMMARY: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.

Tuberous sclerosis complex protein 1 expression is affected by VHL Gene alterations and HIF-1α production in sporadic clear-cell renal cell carcinoma.

Alterations in von Hippel-Lindau gene (VHL) do not determine deregulation of hypoxia-inducible factors (HIFs) in clear-cell renal carcinoma (ccRCC). Their effects on tuberous sclerosis proteins (TSC1/2) and heat shock protein 90 (Hsp90) expressions in sporadic ccRCC are unknown. Therefore, we analyze the impact of VHL alterations and HIF-α production on the expression of TSC proteins and Hsp90 in these tumors. Alterations in VHL gene region exhibited 37/47 (78.7%) tumors. Monoallelic inactivation (intragenic mutation or LOH) was found in 10 (21.3%) and biallelic inactivation (intragenic mutation plus LOH) in 27 (57.4%) ccRCCs. Tumorous expression of HIF-α mRNAs, HIF-α, Hsp90 and TSC2 were VHL independent; TSC2 was underexpressed in all tumors by immunostaining (P<0.001). Immunoblotting revealed that TSC1 production was lower in tumors with monoallelic VHL inactivation than in control (P=0.01) and tissues with biallelic VHL inactivation (P=0.019), while tumors lacking HIF-1α (16/47) concurrently overexpressed HIF-2α and underexpressed TSC1 in comparison to controls (P=0.01 for both) and HIF-1α positive tumors (P=0.015 and P=0.050). Significant portion of variability (56.4%) in tumor diameter was explained by oscillations in nuclear grade, and TSC1 and HIF-2α expression in VHL altered tumors. In conclusion, while TSC2 is broadly downregulated in sporadic ccRCC, TSC1 expression is reduced in two subsets of these tumors, those with monoallelic VHL gene inactivation and those with concurrent low HIF-1α and high HIF-2α expression. Hence, the involvement of nuclear grade, TSC1 and HIF-2α in the progression of VHL altered tumors, implies the interplay between pVHL and TSC1.

Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

Partial versus radical nephrectomy for pT1a renal cancer in Serbia.

PURPOSE: To assess the treatment outcome of pT1a renal tumors, comparing overall survival (OS) in patients treated with radical nephrectomy (RN) and partial nephrectomy (PN), and to examine the rate of utilization of PN in a tertiary institution in Serbia. METHODS: Included were patients treated for pT1a kidney tumors with open RN or open PN during 1996-2013. The inclusion criterion was the pathological tumor stage T1a. Exclusion criteria were higher pathological stages, metastatic presentation, or imperative indications for partial nephrectomy. Patients were followed-up every 3 to 4 months for the first year after surgery, every 6 months until the 5th year, and annually thereafter. RESULTS: 286 patients were included in the study, and PN was performed in 177 (61.9%) of them, whereas RN was performed in the remaining 109 (38.1%). The median follow- up for the entire group was 42.0 months (interquartile range 74.5). There were no statistically significant differences between groups in cancer-specific survival (CSS) (log-rank=0.506; p=0.477). Patients selected for RN were more likely to be older, symptomatic at presentation, and have larger tumors. There was no statistically significant difference in OS between the two groups (log-rank=2.616; p=0.106). In 1996, 20% of the patients were treated with PN; this number increased to 88% in 2013. CONCLUSION: We did not find OS advantage for PN compared to RN in the setting of a developing country. The use of PN is increasing and is now utilized for ∼90% of pT1a renal tumors.

Cross-cultural adaptation and validation of the Serbian version of the Australian pelvic floor questionnaire.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to cross-culturally adapt and validate the Serbian version of the Australian pelvic floor questionnaire. METHODS: The Australian pelvic floor questionnaire was translated according to the standard method of back-translation. Women who presented with pelvic floor disorders completed the Serbian version of the Australian pelvic floor questionnaire. Women were subjected to clinical and gynecological assessment including physical examination, cough stress test, pelvic prolapse anatomical assessment using the Pelvic Organ Prolapse Quantification system, and post-void residual volume. Reliability and divergent validity was performed on 76 patients with significant pelvic floor dysfunction and 23 women without pelvic floor dysfunction. Patients repeated the questionnaire after 4 weeks. RESULTS: High reliability was observed in all four dimensions (Cronbach's alpha coefficients were above 0.8 for each dimension: bladder 0.846, bowel 0.822, prolapse 0.842, and sexual function 0.823). Test-retest analyses revealed high reproducibility (intraclass correlation coefficients were above 0.9). Prolapse symptom score correlated significantly with pelvic organ quantification and bladder score correlated significantly with the results of the cough stress test (convergent validity). Scores distinguished between patients with pelvic floor disorders and controls (high discriminant validity). CONCLUSIONS: The Serbian version of the Australian pelvic floor questionnaire is a reliable and valid instrument for assessment of quality of life in women with pelvic floor disorders.

Testis sparing surgery in the treatment of bilateral testicular germ cell tumors and solitary testicle tumors: A single institution experience.

BACKGROUND AND OBJECTIVE: To assess the oncologic and functional outcomes of testicular sparing surgery (TSS) based on a single institution experience. METHODS: Forty-one patients with bilateral and 3 patients with solitary testicle tumors were referred to our institution. The inclusion criteria for TSS were normal serum testosterone levels, and tumor size (<2 cm). Sperm analysis and hormone status evaluation were performed preoperatively and postoperatively. None of the patients underwent local radiation therapy following TSS for reasons of fertility preservation. RESULTS: A total of 26 TSS were performed in 24 patients. The median follow-up period was 51.0 months. Seven patients developed local recurrence, of which 5 had TIN and were subjected to radical orchiectomy, whereas re-do TSS was done in remaining 2 patients. The overall survival of the study group was 100%, and the presence of testicular intraepithelial neoplasia (TIN) was associated with worse recurrence-free survival (P=0.031, log-rank). Testosterone values were normal in all of the patients, while 4 patients achieved conception. CONCLUSIONS: TSS is acceptable from an oncological point of view, and it enables continuation of a patient's life without lifelong hormonal substitution. Additionally, local irradiation therapy could be delayed in patients with TIN who wish to father children, but with high local recurrence rate.

Surgical treatment of female stress urinary incontinence: retropubictransvaginal tape vs. transvaginal tape obturator.

AIM: To compare two different operative techniques for stress urinary incontinence in women, transvaginal tape obturator(TVT-O) and retropubictransvaginal tape(TVT). METHODS: The study included 63 women, of which 32 received TVT-O and 31 were treated with TVT. Follow-up for all patients was done after 1, 3, 6 and 12 months, and yearly thereafter. Each visit included objective evaluations (post-voig residual and stress test). RESULTS: The average operating time was 13.19±3.72 minutes in TVT-O group and 26.92±4.77 minutes for TVT. Average time of catheter removal was 1.19±0.4 and 1.26±0.44 for TVT-O and TVT, respectively. Average hospital stay was 2.38±0.75 days in TVT-O group and 2.03±0.91 for TVT. Appearance of complications such as trauma of urethra, bladder perforation, injury of vessels, hematoma and wound infection were not registered. Two (6.3%) of the patientswho underwent TVT-O had urinary infection. One (3.1%) of the patients who underwent TVT-O had pelvic pain. De novo urgency appeared in five(15.6%)patients for TVT-O and in four (12.9%) patients for TVT. The success rate in TVT-O group was 90.6% and 90.3% for TVT. CONCLUSION: Both procedures hada very high success rate, with a low rate of perioperative and late postoperative complications.

GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and susceptibility to smoking-related bladder cancer: a case-control study.

OBJECTIVES: Glutathione S-transferases (GSTs) are a family of enzymes involved in detoxification. Genes encoding for GSTA1, GSTM1, GSTP1, and GSTT1 proteins are polymorphic, which can result in complete or partial loss of enzyme activity. Previous studies have associated polymorphisms of GSTA1, GSTM1, and GSTP1 genes with a higher risk of bladder cancer, but this is still controversial. Potential role of GSTA1 polymorphism in susceptibility to bladder cancer in Whites is lacking. We examined association between GSTA1, GSTM1, GSTP1, and GSTT1 gene variants and bladder cancer risk and evaluated whether they were modified by smoking. MATERIALS AND METHODS: A hospital-based case-control study recruited 201 incidence cases and 122 age-matched controls. Deletion polymorphism of GSTM1 and GSTT1 was identified by polymerase chain reaction method. Single nucleotide polymorphism of GSTA1 and GSTP1 was identified by restriction fragment length polymorphism method. Uniconditional multivariate logistic regression was applied to model association between genetic polymorphisms and bladder cancer risk, as well as effect modification by smoking. RESULTS: No significant difference was observed in the distributions of GSTM1, GSTT1, GSTA1, and GSTP1 gene variants between patients and controls. None of the examined polymorphisms was significantly associated with bladder cancer risk independently. The results of gene-smoking interaction analyses indicated a significant combined effect of smoking and all common GST polymorphisms tested (P for trend = 0.001). However, the most significant effect on bladder cancer risk was observed in smokers carrying lower activity GSTA1-AB/BB and GSTM-null genotype (OR = 3.5, P < 0.05) compared with GSTA1-AA and GSTM1-active non-smokers. Overall, the risk observed did not significantly differ with respect to quantity of cigarettes smoked. However, heavy smokers with GSTM1-null genotype had 2 times higher risk of bladder cancer than GSTM1-null light smokers (OR = 4.8 vs. OR = 2.0) when GSTM1-active non-smokers served as reference group. Smokers carrying both GSTM1-null and GSTA1-AB + BB genotypes exhibited the highest risk of bladder cancer (OR = 2.00, P = 0.123). CONCLUSIONS: Null or low-activity genotypes of the GSTA1, GSTM1, GSTT1, and GSTP1 did not contribute independently towards the risk of bladder cancer in our patients. However, in association with smoking, both low activity GSTA1 and GSTM1-null genotype increase individual susceptibility to bladder cancer.

Urinary prostate-specific antigen: predictor of benign prostatic hyperplasia progression?

INTRODUCTION: Urinary prostate-specific antigen (uPSA) can be used as additional parameter of benign prostatic hyperplasia (BPH) progression. MATERIALS AND METHODS: From January 2001 to December 2011, uPSA was determined in 265 patients with benign prostate. Based on total prostate volume (TPV), the patients with benign prostate were divided in two groups: TPV < 31 mL and TPV ≥ 31 mL. Additional three groups were formed upon MTOPS study criteria: non- progressive BPH group (TPV < 31 mL, PSA < 1.6 ng/mL, age < 62 yrs), intermediate group (one, or two parameters {TPV, PSA, age} increased) and progressive BPH group (TPV ≥ 31 ml, PSA ≥ 1.6 ng/mL, age ≥ 62 yrs). RESULTS: Average uPSA values in the groups TPV < 31 mL and TPV ≥ 31 mL were 119.3 ± 124.5 and 255.5 ± 204.9 ng/mL, respectively and they were significantly different (p < 0.0001). Average uPSA values in the non- progressive BPH group, intermediate group and progressive BPH group were 86.8 ± 82.4 ng/mL, 166.6 ± 164.9 ng/mL and 274.9 ± 208.3 ng/mL, respectively and they were significantly different (p < 0.0001). The level of uPSA correlated significantly with TPV (r = 0.32, p < 0.0001). The cut off uPSA level of 150 ng/mL discriminates the patients with non-progressive BPH and progressive BPH with specificity of 0.83 and sensitivity of 0.67. CONCLUSION: The level of uPSA reflects prostatic hormonal activity and correlates with TPV, PSA and age. UPSA level ≥ 150 ng/mL can be used as additional predictive parameter of BPH progression.

Genetic variation in circadian rhythm genes CLOCK and ARNTL as risk factor for male infertility.

BACKGROUND: The circadian system has a major role in maintaining homeostasis and proper body functions including reproductive capacity. The aim of this study was to examine whether there is an association between genetic variability in the primary clock genes CLOCK and ARNTL and male infertility in humans. METHODOLOGY/PRINCIPAL FINDINGS: We performed a case-control study, where we searched for an association between polymorphisms of CLOCK and ARNTL genes and male infertility in 961 Slovenian and Serbian Caucasian men. The study group consisted of 517 patients with idiopathic infertility and a control group of 444 fertile men. A statistically significant difference was found in genotype distribution between the two groups in the CLOCK gene: rs11932595 (p = 6·10(-5), q = 4·10(-4), OR equaled 1.9 with 95% CI 1.4-2.7), rs6811520 (p = 2·10(-3), q = 8·10(-3), OR = 1.7 with 95% CI 1.2-2.2) and rs6850524 (p = 0.01, q = 0.02, OR = 1.4 with 95% CI 1.1-1.9). Further analyses of haplotypes were consistent with genotyping results. CONCLUSIONS/SIGNIFICANCE: We provide evidence that genetic variability in the CLOCK gene might be associated with male infertility warranting further confirmation and mechanistic investigations.

Health-related quality of life, depression, and sexual function in testicular cancer survivors in a developing country: a Serbian experience.

PURPOSE: The aims of this study were to assess health-related quality of life (HRQoL), depression, adverse physical symptoms, and sexual function within Serbian long-term testicular cancer survivors (TCS) and to address cultural specificity. METHODS: This is a cross-sectional study involving 202 TCS, followed up after platinum-based chemotherapy. The HRQoL was measured using the Short Form 36 and the European Organization for Research and Treatment of Cancer Quality of Life questionnaire. The Beck Depression Inventory (BDI) was used to explore general depressive status while sexual function was assessed using a nine-item questionnaire. RESULTS: The mean follow-up time since treatment was 47.3 ± 26.8 months. The highest values of the SF-36 scales were obtained for physical functioning, and the lowest SF-36 values were obtained for vitality. Age of patients and BDI scores statistically significantly influenced total quality of life. The mean score of the whole sample on the BDI-II was 4.0. Age is the only statistically significant risk factor for the development of depression. A total of 27.3% TCS reported decreased sexual function compared to the period before treatment. Any level of impairment of erectile function was reported by 20.8% patients and problems with ejaculation by 25.7% patients. Loss of desire was reported by 17.3% TCS. The presence of sexual problems statistically significantly lowered scores of SF-36 domains. CONCLUSION: Sexual problems seriously impaired HRQoL in TCS. Additionally, HRQoL was also affected by age, depression, and fatigue. Serbian TCS achieved high levels of SF-36 scores, and these results are comparable to studies conducted in developed countries.

Prognostic significance of non-muscle-invasive bladder tumor history in patients with upper urinary tract urothelial carcinoma.

OBJECTIVE: To evaluate the prognostic factors for survival and disease recurrence in patients treated surgically for upper tract urothelial carcinoma (UTUC), focusing especially on the impact of history of non-muscle-invasive bladder cancer. PATIENTS AND METHODS: A single-center series of 221 consecutive patients who were treated surgically for UTUC between January 1999 and December 2010 was evaluated. Patients who had a history of bladder tumor at a higher stage than the upper tract disease, preoperative chemotherapy, or previous contralateral UTUC were excluded. None of the patients included in this study had distant metastasis at diagnosis of UTUC. In total, 183 patients (mean age 66 years, range 36-88) were then available for evaluation. Tumor multifocality was defined as the synchronous presence of 2 or more pathologically confirmed tumors in any upper urinary tract location (renal pelvis or ureter). All patients were treated with either open radical nephroureterectomy (RNU) or open conservative surgery. Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan-Meier method and Cox regression analyses. RESULTS: Fifty-one patients (28%) had previous carcinoma not invading bladder muscle. Previous history of non-muscle-invasive bladder cancer was significantly associated with tumor multifocality (P < 0.001), concomitant bladder cancer (P < 0.001), higher tumor stage (P = 0.020), and lymphovascular invasion (P = 0.026). Using univariate analyses, history of non-muscle-invasive bladder cancer was significantly associated with an increased risk of both any recurrence (HR = 2.17; P = 0.003) and bladder-only recurrence (HR = 3.17; P = 0.001). Previous carcinoma not invading bladder muscle (HR = 2.58; P = 0.042) was an independent predictor of bladder-only recurrence. Overall 5-year disease recurrence-free (any recurrence and bladder-only recurrence) survival rates were 66.7% and 77%, respectively. Previous history of non-muscle-invasive bladder cancer was not associated with cancer-specific survival. Our results are subject to the inherent biases associated with high-volume tertiary care centers. CONCLUSIONS: Patients with previous history of non-muscle-invasive bladder cancer had a higher risk of having multifocal and UTUC with higher tumor stages (pT3 or greater). History of bladder tumor was an independent predictor of bladder cancer recurrence but had no effect on non-bladder recurrence, and cancer-specific survival in patients who underwent surgical treatment of UTUC.

Rapidly progressive course of primary renal synovial sarcoma--case report.

INTRODUCTION: Primary kidney sarcoma, especially synovial sarcoma (SS), is a very rare neoplasm. Preoperative signs and symptoms are very similar to renal cell carcinoma, therefore, the proper diagnosis is very difficult and usually made after nephrectomy.This is a case report of primary renal SS. CASE OUTLINE: A 38-year-old man presented with a history of fever and hematuria, and right flank pain 3 weeks ago. Abdominal computerized tomography revealed a heterogeneous well-marginated soft tissue mass arising in the lower part of the right kidney. Right nephrectomy was performed. A cystic tumor of 120 x 85 mm in size with soft solid growth, and with the extensive areas of hemorrhage and necrosis was seen on gross examination. Histopathology revealed a neoplasm composed of solid monomorphic sheets of spindle cells. Immunohistochemistry showed tumor cells strongly positive for BCL2, CD99, CD56 and vimentin, and focally positive for epithelial membrane antigen (EMA). The histological diagnosis of primary renal SS was based on morphology and immunohistochemistry. FISH analysis and RT-PCR was carried out on formalin-fixed paraffin-embedded tissue sections. The molecular analysis demonstrated translocation of SYT gene on chromosome 18 and SSX2 gene on chromosome X. The findings were consistent with diagnosis of SS. CONCLUSION: Our case shows that histopathological diagnosis of primary kidney SS, although difficult, is possible to be made on the basis of morphological and immunohistochemical analysis. However, this diagnosis should be corroborated by molecular techniques confirming SYT-SSX translocation on chromosome 18 and chromosome X. Here we present visceral monophasic SS with aggressive clinical course and poor outcome.

Expression of neural cell adhesion molecule in renal cell carcinoma.

Neural cell adhesion molecule (NCAM) is important for cell migration and it could be expressed in some renal cell carcinoma (RCC). In recent decades, the incidence of RCC has been steadily rising by 2-4% each year. In this study NCAM expression and correlation with nuclear grade in different RCC were analyzed. We analyzed NCAM expression on 7 different RCC cell lines and 32 different RCC by immunohistochemistry, immunofluorescence, Western blot and FACS analysis. NCAM expression is detected in 6 cell lines and 16 RCC cases. NCAM-140 kDa isoform is expressed in different RCC and RCC cell lines. NCAM expression in non-invasive clear cell RCC is lower than in clear cell RCC with high nuclear grade. Expression of NCAM is not exclusive for specific RCC type, so NCAM can not be used as a specific diagnostic marker for RCC. NCAM expression is in correlation with nuclear grade in clear cell RCC, suggesting that NCAM expression is involved in aggressive behavior and metastatic potential in RCC.

Glycosaminoglycans in the urinary bladder mucosa, tumor tissue and mucosal tissue around tumor.

INTRODUCTION/AIM: Glycosaminoglycans (GAG) are one of the main constituents of the connective tissue and cellular membrane. Their presence has been evidenced in mucosa and muscular tissue of the urinary bladder of both healthy individuals and those affected by carcinoma. This suggest their potential role in the onset of bladder carcinoma and follow-up of those patients. The aim of the study was to determine GAG levels in tumor tissue and the surrounding bladder mucosa in patients with bladder tumor, as well as in the bladder mucosa in patients with bladder carcinoma, and to compare the results according to the grade and stage of tumor and relapse. METHODS: Tissue samples were taken in 61 patients (48 males and 13 females), mean age 61.5 years, range 40-92 years, obtained by transurethral resection (TUR) of bladder tumor, and 8 healthy persons. Determination of a total GAG content in the tissue samples was done by the Whiteman's method and then compared regarding the tumor grade and stage. RESULTS: Tumor grade and stage directly correlated with the levels of GAG. The GAG levels were significantly higher in tumor samples as compared to healthy mucosa. CONCLUSION: Higher GAG levels were recorded in all the patients with bladder tumors comparing to samples obtained from healthy individuals. GAG levels do not predict tumor relapse.

Morphology of Balkan endemic nephropathy: current state.

Balkan endemic nephropathy (BEN) is interesting renal disease, because of its unique clinical, epidemiological and morphological characteristics: intensive interstitial fibrosis and tubular atrophy without any inflammation. In the present paper we evaluate the incidence of BEN from the morphological point of view for the last decade. Therefore we analyzed material obtained from autopsies, kidney biopsies and nephrectomy due to upper urothelial cancer (UUC) from the patients which were divided into two groups: those with permanent residence in BEN areas and those from nonendemic areas. At the Institute of Pathology, University of Belgrade for the last 15 years we had only 1 autopsy due to BEN out of 6,825. More than 30 years ago there were over 50 autopsy cases of BEN at the same institute. For the last decade we had only 2 kidney biopsies suspected for BEN out of 2,182, but morphologically not confirmed as BEN. However, previously we had over 40 kidney biopsies diagnosed as early or late stage of BEN. At the Clinical Center of Serbia 180 nephrectomies were performed due to UUC. The incidence of UUC for the last five years in BEN regions has significantly decreased, whereas at the same time in non-BEN regions it has remained on the same level. There was no morphological difference of the renal tissue adjacent to tumor between patients from BEN and non-BEN regions. According to our study based on routine pathological work, we could clearly conclude that BEN today is more clinical and epidemiological than a morphological entity.

Upper urinary tract transitional cell carcinoma: location is not correlated with prognosis.

OBJECTIVE: To identify the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for upper urinary tract transitional cell carcinoma (UUT-TCC). PATIENTS AND METHODS: A single-centre series of 189 consecutive patients who were treated surgically for UUT-TCC between January 1999 and December 2009 was evaluated. Patients who had previously undergone radical cystectomy, preoperative chemotherapy or contralateral UUT-TCC were excluded. In all, 133 patients were available for evaluation. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour. Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan-Meier method and Cox regression analyses. RESULTS: The 5-year recurrence-free and cancer-specific survival estimates for the cohort in the present study were 66% and 62%, respectively. The 5-year bladder-only recurrence-free probability was 76%. Using multivariate analysis, only pT classification (hazard ratio, HR, 2.46; P = 0.04) and demographic characteristics (HR, 2.86 for areas of Balkan endemic nephropathy, vs non-Balkan endemic nephropathy areas; 95% confidence interval, 1.37-5.98; P = 0.005) were associated with disease recurrence. Tumour location was not associated with disease recurrence in any of the analyses. There was no difference in cancer-specific survival between renal pelvis and ureteral tumours (P = 0.476). Using multivariate analysis, pT classification (HR, 8.04; P = 0.001) and lymph node status (HR, 4.73; P = 0.01) were the only independent predictors associated with a worse cancer-specific survival. CONCLUSION: Tumour location is unable to predict outcomes in a single-centre series of consecutive patients who were treated with radical nephroureterectomy for UUT-TCC.

Renal cancer and Wegener's granulomatosis: a case report.

Wegener's granulomatosis (WG) is a systemic disorder characterized by necrotizing vasculitis involving the respiratory tract, and in most cases, the kidneys. The most common manifestation of WG in the kidneys is segmental necrotizing glomerulonephritis. The presence of a renal mass as a manifestation of WG is rare. We report a patient with WG in whom a CT scan revealed an infiltrating mass in the lower portion of the left kidney. After surgical exploration, we performed an open radical nephrectomy. Histopathology showed clear cell type renal cell carcinoma (RCC). RCC associated with WG has been reported in only a few cases, and in most of them, the diseases started simultaneously, suggesting common pathogenetic pathways. Long-term immunosuppressive treatment is a known risk factor in the development of malignancies, so occurrence of RCC in WG has been proposed as a side effect of cyclophosphamide treatment. Furthermore, it is important to make a differential diagnosis between RCC and pseudotumors in WG as they cannot be distinguished solely on basis of imaging findings. Due to the higher risk of urologic malignancies, more frequent checkups and screening of WG patients should be considered.